Paclitaxel is a diterpene taxane found in very low concentration in the bark of Pacific yew tree Taxus brevifolia. Therefore, a number of semi-synthetic strategies have been developed for its synthesis from more readily available 10-DAB. However, the taxane nucleus is highly prone to degradation and semis-synthetic crude materials are often produced contaminated with structurally similar impurities, thereby necessitating elaborate purification procedure using HPLC. In view of the above facts it becomes highly desirable to develop alternative routes for synthesis of paclitaxel which involves minimal degradation along the synthetic pathway.
Any synthetic protocol for the semi-synthesis of paclitaxel/docetaxel generally consists of
a) selective acylation/protection at similarly reactive C-7 and C-10 hydroxyl groups. Among the 1, 7, 10 and 13-hydroxyl groups in 10-DAB, the order of reactivity is 7>10>13>1. Therefore, selective esterification of 13-hydroxyl group requires prior protection of both 7 and 10-hydroxyl groups. Furthermore, if acetyl group is required in the final product, as in the case of paclitaxel, then 7-hydroxyl is to be protected first followed by acetylation of 10-hydroxyl. This requires selection of appropriate protecting groups, which can be put selectively and removed selectively under mild condition. Recently, we have explored the use of haloalkyl acid chlorides as protecting groups (U.S. Provisional patent Application 60/311,077). These haloalkonoyl groups undergo hydrolysis faster than unsubstituted alkonoyl groups and their deprotection causes minimum degradation. We have found that such haloalkyl acid chlorides specifically 2-haloalkyl acid chlorides can be used for selective protection in taxanes and can be selectively deprotected.b) selective esterification of 13-hydroxyl group with a suitably protected N-benzoylphenylisoserine. It has been found that α-hydroxy-β-amidoaryl moiety at the 13-hyroxyl of the taxane moiety is essential for its anti-cancer activity (Wani et. al J. Am. Chem. Soc. 93, pp 2325, 1971). Esterification at 13-hydroxyl of taxane is very sluggish due its stereo-electronic disposition. It is known from literature that esterification step proceeds to completion with cyclic forms of α-hydroxy-β-amidoarylcarboxylic acids. Furthermore, when cyclic forms of C-13 side chain is used, no 2′-epimers is obtained as side product. Therefore, new cyclic forms of side chains, which undergo facile coupling with suitably protected 10-DAB in high yield under simple reaction condition without their use in large excess, are required for developing better and more efficient alternative routes for synthesis of paclitaxel and its analogs.c) conversion of side chain precursor part into side chain and removal of the protecting groups from baccatin part. These reaction conditions should be mild in nature to afford final material in high yield with very few side products. For successful commercial production, it is desirable that the crude semi-synthetic taxane is produced with such purity that it could easily be purified into pharmaceutical grade material.
Most of the nitrogen protecting groups used so far in oxazolidine carboxylic acid require either harsh acidic condition or hydrogenolysis for their removal.
Thus, e.g. U.S. Pat. No. 5,476,954 to Bourzat et al describes an oxazolidine side chain having a tert-butoxy carbonyl protecting group on the nitrogen atom. After coupling with suitably protected 10-DAB, this protecting group is removed by treating the coupled product in 98% formic acid medium and removal of acid by evaporation to obtain an amine which is then converted into the corresponding benzoyl derivative. The harsh acidic condition reaction and evaporation decomposed the free amine and resulted in the final product with close taxane related impurities.
Also, Mas et al. in the U.S. Pat. No. 5,616,739 describes a process in which the coupled product, obtained from coupling of an oxazolidine sidechain having a 2-trichloroethoxy carbonyl group and a protected 10-DAB. The resulting coupled product undergo reductive cleavage by using Zn-acetic acid to achieve simultaneous removal of side chain protecting groups and 7/10-hydroxyl protecting group. The resultant amine is then suitably protected to obtain the taxane. The disadvantage of this process is the free amine obtained in the above process where the 7/10 position is open. The free amine degrade very fast when the protection of 7/10 position is open and a number of decomposition product are formed.
On the other hand, U.S. Pat. No. 5,637,723 issued to Rhone Poulenc Rorer S. A. in 1997 described an oxazolidine carboxylic acid, which incorporated benzoyl group as the nitrogen-protecting group. Consequently, the coupled product obtained from the oxazolidine carboxylic acid and protected 10-DAB, upon deprotection did not require to be protected by a benzoyl group. Again this procedure requires deprotection of the coupled product in an acidic medium and is applicable only to Paclitaxel since the benzoyl group is inactive and hard to remove.
With a view to develop side chain precursor which can be processed to paclitaxel/docetaxel after coupling with suitably protected taxane, under very mild acid and preferably neutral condition, the applicants have found the following oxazolidine carboxylic acid of general structure 1. It has a (2-trialkylsilyl)ethoxycarbonyl/(2-phenyl-2-trialkylsilyl)ethoxycarbonyl group as nitrogen protecting group, which can be cleaved under very mild condition, and therefore degradation of taxane nucleus
can be avoided. The other N, O-bifunctional protecting group then undergoes cleavage very fast without degradation under mild condition.
(2-Trialkylsilyl)ethoxycarbonyl groups are more labile than t-butoxy carbonyl and 2-trichloroethoxy carbonyl nitrogen protecting group reported in prior art. In fact (2-phenyl-2-trialkylsilyl) ethoxycarbonyl group can be cleaved under almost neutral condition.
Therefore, these oxazolidine carboxylic acids have emerged as new type of side chain precursor for the synthesis of paclitaxel and docetaxel.
Herein the applicant have described new intermediates for taxoid anticancer drugs, their process of synthesis and process for synthesis of paclitaxel and similar analogs using them (Scheme-1).